Up-regulation of vascular endothelial growth factor-D expression in clear cell renal cell carcinoma by CD74: a critical role in cancer cell tumorigenesis.
Elevation of CD74 is associated with a number of human cancers, including clear cell renal cell carcinoma (ccRCC). To understand the role of CD74 in the oncogenic process of ccRCC, we ectopically expressed CD74 in human embryonic kidney 293 cells (HEK/CD74) and evaluated its oncogenic potential. Through overexpression of CD74 in HEK293 and Caki-2 cells and down-regulation of CD74 in Caki-1 cells, we show that vascular endothelial growth factor-D (VEGF-D) expression is modified accordingly. A significant, positive correlation between CD74 and VEGF-D is found in human ccRCC tissues (Pearson's correlation, r = 0.65, p < 0.001). In HEK/CD74 xenograft mice, CD74 significantly induced the formation of tumor masses, increased tumor-induced angiogenesis, and promoted cancer cell metastasis. Blockage of VEGF-D expression by small interference RNA resulted in a decrease in cell proliferation, invasion, and cancer cell-induced HUVEC migration enhanced by CD74. Furthermore, we provide evidence that the intracellular signaling cascade responsible for VEGF-D up-regulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-kappaB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.
Liu
Yu-Huei
YH
Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lin
Chang-Yueh
CY
Lin
Wei-Chou
WC
Tang
Sai-Wen
SW
Lai
Ming-Kuen
MK
Lin
Jung-Yaw
JY
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000008:administration & dosage / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000008:administration & dosage / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D042643:Vascular Endothelial Growth Factor D; C045084:invariant chain